EP1844050B1 - Pyrrolopyrimidines useful as inhibitors of protein kinase - Google Patents
Pyrrolopyrimidines useful as inhibitors of protein kinase Download PDFInfo
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- EP1844050B1 EP1844050B1 EP06734381A EP06734381A EP1844050B1 EP 1844050 B1 EP1844050 B1 EP 1844050B1 EP 06734381 A EP06734381 A EP 06734381A EP 06734381 A EP06734381 A EP 06734381A EP 1844050 B1 EP1844050 B1 EP 1844050B1
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- 0 *[n]1c2ncnc(Cl)c2cc1 Chemical compound *[n]1c2ncnc(Cl)c2cc1 0.000 description 10
- UQXFFUGBLGBDGK-UHFFFAOYSA-N C(Cc1c(cc[nH]2)c2ncn1)C1OCCCO1 Chemical compound C(Cc1c(cc[nH]2)c2ncn1)C1OCCCO1 UQXFFUGBLGBDGK-UHFFFAOYSA-N 0.000 description 1
- XDNJTJMNBGHEHE-UHFFFAOYSA-N C1CC(c2c(cc[nH]3)c3ncn2)=CC1 Chemical compound C1CC(c2c(cc[nH]3)c3ncn2)=CC1 XDNJTJMNBGHEHE-UHFFFAOYSA-N 0.000 description 1
- BOZXYFLTTUWLOK-UHFFFAOYSA-N C=C(c1ccccc1)c1c(cc[nH]2)c2ncn1 Chemical compound C=C(c1ccccc1)c1c(cc[nH]2)c2ncn1 BOZXYFLTTUWLOK-UHFFFAOYSA-N 0.000 description 1
- NOZGUEOAJZDEEP-UHFFFAOYSA-N C=Cc1c([CH]C=N2)c2ncn1 Chemical compound C=Cc1c([CH]C=N2)c2ncn1 NOZGUEOAJZDEEP-UHFFFAOYSA-N 0.000 description 1
- WPGBWOIWWHJBKI-UHFFFAOYSA-N CC1C(N)=CCC1 Chemical compound CC1C(N)=CCC1 WPGBWOIWWHJBKI-UHFFFAOYSA-N 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N CC1CCCC1 Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- UAEPNZWRGJTJPN-UHFFFAOYSA-N CC1CCCCC1 Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 1
- QFXRPIZCVCYLHN-UHFFFAOYSA-N CNC1=CCCC2C1CCC2 Chemical compound CNC1=CCCC2C1CCC2 QFXRPIZCVCYLHN-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Definitions
- the present invention relates to compounds useful as inhibitors of Janus kinases (JAK).
- the invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
- the Janus kinases are a family of tyrosine kinases consisting of JAK1, JAK2, JAK3 and TYK2.
- the JAKs play a critical role in cytokine signaling.
- the down-stream substrates of the JAK family of kinases include the signal transducer and activator of transcription (STAT) proteins.
- STAT signal transducer and activator of transcription
- JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis as well as in solid and hematologic malignancies such as leukemias and lymphomas.
- JAK2 has also been implicated in myeloproliferative disorders, which include polycythemia vera, essential thrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome and systematic mast cell disease.
- Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) family are effectors of Ras-related small GTPase Rho.
- the ROCK family includes p160ROCK (ROCK-1), ROK ⁇ /Rho-kinase/ROCK-II, protein kinase PKN, and citron and citron kinase.
- ROCK has been implicated in various diseases and disorders including hypertension, chronic obstructive pulmonary disease, cerebral vasospasm, coronary vasospasm, bronchial asthma, erectile dysfunction, glaucoma, vascular smooth muscle cell proliferation, myocardial hypertrophy, malignoma, ischemia/reperfusion-induced injury, endothelial dysfunction, Crohn's Disease and colitis, neurite outgrowth, Raynaud's Disease, angina, Alzheimer's disease, atherosclerosis, and cardiac hypertrophy and perivascular fibrosis.
- PKA Protein kinase A
- cAMP-dependent protein kinase is a tetrameric holoenzyme, which contains two catalytic subunits bound to a homo-dimeric regulatory subunit (which acts to inhibit the catalytic sub-units).
- cAMP enzyme activation
- the catalytic subunits dissociate from the regulatory subunits to yield the active serine/threonine kinase.
- Three isoforms of the catalytic subunit C- ⁇ , C- ⁇ and C- ⁇
- PKA has been shown to regulate many vital functions including energy metabolism, gene transcription, proliferation, differentiation, reproductive function, secretion, neuronal activity, memory, contractility and motility.
- WO 01/42246 A2 describes pyrrolo[2,3-d]pyrimidine compounds which are inhibitors of the enzyme protein kinases such as Janus Kinase 3 and as such are useful therapy as immunosuppressive agents for organ transplants, xeno transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Chrohn's disease, Alheimer's disease, Leukemia and other indications where immunosuppression would be desirable.
- compounds of this invention are effective as inhibitors of protein kinases, particularly the JAK family kinases.
- these compounds are effective as inhibitors of JAK3 protein kinases.
- These compounds have the general formula I : or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , Z 1 , Z 2 , and Z 3 are as defined below.
- These compounds, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of a variety of disorders, including allergic disorders such as asthma and atopic dermatitis, autoimmune diseases such as SLE lupus and psoriasis, conditions associated with organ transplantation, myeloproliferative disorders, hypertension, chronic obstructive pulmonary disease and proliferative disorders such as melanoma.
- allergic disorders such as asthma and atopic dermatitis
- autoimmune diseases such as SLE lupus and psoriasis
- conditions associated with organ transplantation myeloproliferative disorders
- hypertension chronic obstructive pulmonary disease
- proliferative disorders such as melanoma.
- compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
- substituents such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
- phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.”
- substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
- an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
- Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
- stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
- a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
- a bond drawn from a substituent to the center of one ring within a multiple-ring system represents substitution of the substituent at any substitutable position in any of the rings within the multiple ring system.
- Figure a represents possible substitution in any of the positions shown in Figure b .
- each substituent only represents substitution on the ring to which it is attached.
- Y is an optionally substituent for ring A only
- X is an optional substituent for ring B only.
- aliphatic or "aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms.
- Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Further examples of aliphatic groups include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, and sec-butyl.
- cycloaliphatic refers to a monocyclic C 3 -C 8 hydrocarbon or bicyclic C 8 -C 12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members.
- Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Further examples of aliphatic groups include cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cycloheptenyl.
- heterocycle means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members are an independently selected heteroatom.
- the "heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.
- heterocyclic rings include, but are not limited to, the following monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidin
- heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2 H -pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
- unsaturated means that a moiety has one or more units of unsaturation.
- alkoxy refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.
- haloalkyl means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
- halogen means F, Cl, Br, or I.
- aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
- aryl may be used interchangeably with the term “aryl ring”.
- aryl also refers to heteroaryl ring systems as defined herein below. Examples of aryl rings would include phenyl, naphthyl, and the heteroaryl group listed below.
- heteroaryl used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members.
- heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.
- heteroaryl rings include the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl,
- Optional substituents on the aliphatic group of R° are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 ahphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H CO 2 (C 1-4 aliphatic), O(haloC 1-4 aliphatic), or haloC 1 - 4 aliphatic, wherein each of the foregoing C 1-4 aliphatic groups of R° is unsubstituted.
- Optional substituents on the aliphatic group of R * are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(halo C 1-4 aliphatic), or halo(C 1-4 aliphatic), wherein each of the foregoing C 1-4 aliphatic groups of R * is unsubstituted.
- Optional substituents on the aliphatic group or the phenyl ring of R + are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 CN, CO 2 H CO 2 (C 1-4 aliphatic), O(halo C 1-4 aliphatic), or halo(C 1-4 aliphatic), wherein each of the foregoing C 1-4 aliphatic groups of R + is unsubstituted.
- two independent occurrences of R° are taken together with the atom(s) to which each variable is bound to form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Exemplary rings that are formed when two independent occurrences of R° (or R + , or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R° (or R + , or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R°) 2 , where both occurrences of R° are taken together with the nitrogen atom to form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two independent occurrences of R° (or R + , or any other variable similarly defined herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two occurrences of these two occurrences of R° are taken together with the oxygen atoms to which they
- An alkyl or aliphatic chain can be optionally interrupted with another atom or group. This means that a methylene unit of the alkyl or aliphatic chain is optionally replaced with said other atom or group.
- the optional replacements form a chemically stable compound.
- Optional interruptions can occur both within the chain and at either ends of the chain; both at the point of attachment and also at the terminal end. Two optional replacements can also be adjacent to each other within a chain.
- the replacement or interruption occurs at the terminal end, the replacement atom is bound to an H on the terminal end. For example, if -CH 2 CH 2 CH 3 were optionally interrupted with -O-, the resulting compound could be -OCH 2 CH 3 , -CH 2 OCH 3 , or -CH 2 CH 2 OH.
- structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
- the present invention relates to a compound of formula I : or a pharmaceutically acceptable salt thereof, wherein:
- Z 1 , Z 2 , and Z 3 together with the carbon atom to which they are attached, form the bicyclic ring shown in Formula I: wherein
- Q 3 is a cyclopropyl group optionally substituted with 0-2 J Q groups as shown in formula II:
- Z 1 and Z 2 together with the carbon atom to which they are attached, form a monocyclic, bicyclic, or tricyclic ring as shown in formula III: wherein
- Z 11 and Z 12 are each independently carbon.
- Q is C 3-7 monocycle and Q 1 and Q 2 are absent.
- Q and Q 1 together form a fused 6-14 membered bicyclic ring and Q 2 is absent.
- Q, Q 1 , and Q 2 together form a fused 8-20 membered tricyclic ring.
- Z 12 is carbon and the fused ring of Q, Q 1 , and optionally Q 2 is as shown in Formula IV: wherein Q, Q 1 , and Q 2 each independently and optionally contain
- the hydrogen atoms at the point of fusion between ring Q and ring Q 1 is in the cis conformation as shown in Formula V:
- the hydrogen atoms at the point of fusion between ring Q and ring Q 1 are in the trans conformation.
- C-Z 11 is a single bond.
- ring Q contains up to two heteroatoms. In other embodiments, ring Q contains one heteroatom; and in yet other embodiments, ring Q contains zero heteroatoms.
- Q contains two heteroatoms and each of said heteroatoms are independently selected from nitrogen, sulfur, or oxygen; preferably nitrogen and sulfur; more preferably, nitrogen. In some embodiments, both heteroatoms are nitrogen. In other embodiments, one is nitrogen and the other is sulfur. In some embodiments, one heteroatom is nitrogen and the other is oxygen. In yet other embodiments, one heteroatom is nitrogen and the other is sulfur.
- Q contains one heteroatom selected from O, N, or S.
- the heteroatom is oxygen; in other embodiments, the heteroatom is nitrogen; in yet other embodiments, the heteroatom is sulfur.
- the sulfur is optionally substituted with 0,1, or 2 oxo groups.
- heterocyclic groups include piperidine, piperazine, morpholine, thiomorpholine, and pyrrolidine.
- ring Q is a 5-7 membered cycloaliphatic.
- cycloaliphatic groups include cyclohexane, cyclopentane, cyclohexene, and cyclopentene.
- Q 1 is a 6-membered aryl or 5-6 membered heteroaryl ring.
- aryl or heteroaryl rings include include phenyl, pyridine, pyrimidine, thiophene, thiazole, tetrazole, triazole, pyrrole, furan, and pyrazole.
- Q 1 is a 3-7 membered cycloaliphatic ring.
- cycloaliphatic rings include cyclohexane, cyclopentane, cyclohexene, cyclopentene, cycloheptene, cycloheptane, cyclopropane, cyclobutane, cyclopropene, and cyclobutene.
- Q 1 is a 3-7 membered heterocyclic ring.
- heterocyclic groups include piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, homopiperidine, and homopiperazine.
- Q or Q-Q 1 is represented by the following structures: wherein both R 7 and J Q are each independently selected from hydrogen, Y, -(V n )-CN, -(V n )-NO 2 , -(V n )-OH, -(V n )-(C 1-6 aliphatic), -(V n )-(C 3-12 heterocyclyl), -(V n )-(C 6-10 aryl), -(V n )-(5-10 membered heteroaryl), -(V n )-(C 3-10 cycloaliphatic), and -(C 3-10 cycloaliphatic)-(C 3-12 heterocyclyl); wherein for each Q and Q 1 , m is independently 0-3; and each R 7 and J Q is optionally and independently substituted with 0-10 J R groups.
- n is 0, 1, or 2. In another embodiment, m is 1 or 2. In some embodiments, m is 0; in other embodiments, m is 1; in yet other embodiments, m is 2.
- J Q is Y, -(V 1 n )-CN, -(V 1 n )-NO 2 , -(V 1 n )-OH, -(V 1 n )-(C 1-6 aliphatic), -(V 1 n )-(C 3-12 heterocyclyl), -(V 1 n )-(C 6-10 aryl), -(V 1 n )-(5-10 membered heteroaryl), -(V 1 n )-(C 3-10 cycloaliphatic), or -(C 3-10 cycloaliphatic)-(C 3-12 heterocyclyl); wherein
- X is optionally substituted C 1-4 aliphatic. In some embodiments, X is optionally substituted C 1-4 alkyl. In some embodiments, X is optionally substituted C 1-2 alkyl.
- n is 0. In other embodiments, n is 1. In certain embodiments, p is 0. In other embodiments, p is 1.
- J Q is optionally substituted with 0-10 J R groups. In some embodiments, 0-5 J R groups; in other embodiments, 0-3 J R groups; and in yet other embodiments, 0-2 J R groups; In some embodiments, one J R group, and in certain embodiments, 0 J R groups.
- R 1 and R 2 are each independently H, halogen, C 1-4 alkyl, or C 1-4 alkoxy. In one embodiment,R 1 and R 2 are each independently H.
- R 7 is independently selected from Y, -(V 1 n )-CN, -(V 1 n )-NO 2 , -(V 1 n )-OH, -(V 1 n )-(C 1-6 aliphatic), -(V 1 n )-(C 3-12 heterocyclyl -(V 1 n )-(C 6-10 aryl), -(V 1 n )-(5-10 membered heteroaryl), -(V 1 n )-(C 3-10 cycloaliphatic), or -(C 3-10 cycyloaliphatic)-(C 3 - 12 heterocylyl); wherein
- Z 1 and Z 2 do not join to form a ring and Z 3 is H or is absent.
- Z 1 is H or C 1-6 aliphatic optionally substituted with 0-3 J Z groups. In some embodiments, Z 1 is H.
- C ⁇ Z 1 is a triple bond, and Z 2 and Z 3 are absent.
- Z 1 is O; in other embodiments, Z 1 is CH 2 .
- Z 2 is optionally substituted Y, -(V n )-(C 1-6 aliphatic), -(V n )-(C 3-12 heterocyclyl), -(V n )-(C 6-10 aryl), -(V n )-(5-10 membered heteroaryl), or -(V n )-(C 3-10 cycloaliphatic).
- n is 1.
- Z 2 is an optionally substituted 5-7 membered monocycle selected from heterocyclyl, cycloaliphatic, aryl, or heteroaryl; preferably a 5-7 membered fully or partially saturated monocycle selected from heterocyclyl or cycloaliphatic; more preferably, a 6-membered monocycle with 0-2 nitrogen atoms.
- Z 2 is piperidine optionally substituted with 0-3 J Z groups.
- Z 2 is optionally substituted -(V n )-(C 3-10 cycloaliphatic) wherein n is 0.
- Z 2 is a bicyclo-octane ring.
- Z 2 is a C 5-7 cycloaliphatic.
- Z 2 is a C 5-7 cycloalkyl.
- J Z is halogen, CF, optionally substituted C 1-4 haloalkyl, -(V 1 n )-CN, -(V 1 n )-NO 2 , -(V 1 n )-OH, Y, -(V 1 n )-(C 3-12 heterocyclyl), -(V 1 n )-(C 6-10 aryl), -(V 1 n )-(5-10 membered heteroaryl), -(V 1 n )-(C 3-10 cycloaliphatic), or -(C 3-10 cycloaliphatic)-(C 3-12 heterocyclyl); wherein
- X is C 1-5 aliphatic. In certain preferred embodiments, X is C 1-5 alkyl. In other preferred embodiments, X is C 1-2 alkyl.
- R J is C 6-10 aryl or 5-10 membered heteroaryl. In other embodiments, R J is C 1-6 aliphatic or C 3-10 cycloaliphatic. In some embodiments, R J is C 1-6 aliphatic. In other embodiments, R J is C 3-10 cycloaliphatic.
- n is 1. In other embodiments, n is 0.
- Example 1 depicts several methods for the preparation of functionalized quinoxalines.
- Scheme 1 is a representative scheme for the preparation of compounds of this invention.
- Compound 1 which is commercially available, can be protected by a suitable protecting group (e.g. Tosyl) as described in T.W. Greene & P.G.M Wutz, "Protective Groups in Organic Synthesis", 3rd Edition, John Wiley & Sons, Inc. (1999 )) to form compound 2.
- a suitable protecting group e.g. Tosyl
- Boronic acids/esters (5) can be prepared from the corresponding vinyl halides (4b) or vinyl triflates (4a) as described in Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299-6302 ; McMurry, J. E.; Scott, W. J.
- Scheme 2 shows additional methods for the preparation of compounds of this invention.
- other compounds that react with amines can be used to form P 1 substitutions. Examples include, but are not limited to, R'-halogen, R'-tosyl, R'-mesylate, R'S(O) 2 Cl, R'NS(O) 2 Cl, R'OH, R'COOH, and R' CH 2 -halogen.
- Scheme III shows an additional method for preparing compounds of this invention.
- the aryl bromide or iodide can be coupled with substituted terminal alkynes in the presence of palladium, base, and CuI under Sonogashira coupling conditions ( Sonogashira, Kenkichi. "Palladium-catalyzed alkynylation” Editor(s): Negishi, Eiichi. Handbook of Organopalladium Chemistry for Organic Synthesis (2002), 1: 493-529. Publisher: John Wiley & Sons, Inc., Hoboken, N. J .) to form the product as shown. refers to suitable terminal alkynes which are either commercially available or can be made from commercially available starting materials.
- the present invention provides compounds that are inhibitors of protein kinases, including JAK family, ROCK and PKA kinases, particularly JAK2 and JAK3 kinases, and thus the present compounds are useful for the treatment of diseases, disorders, and conditions including, but not limited to, immunodeficiency disorders, inflammatory diseases, allergic diseases, autoimmune diseases, proliferative disorders, immunologically-mediated diseases, respiratory disorders.
- pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.
- a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
- pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt means any non-toxic salt of a compound of this invention.
- Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 , incorporated herein by reference.
- Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
- Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
- Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
- This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
- the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
- a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
- Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980 ) discloses various carriers used in formulating pharmaceutically acceptable composition
- any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
- materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc
- the compounds of pharmaceutically acceptable compositions according of the invention way be used in the manufacture of a medicament for the treatment or lessening the severity of a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, or an immunologically mediated disorder.
- an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, a psychotic disorder, a viral disease, a bone disorder or an immunologically mediated disorder.
- the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, a psychotic disorder, a viral disease, a bone disorder or an immunologically mediated disorder.
- the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
- the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
- dose unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
- the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
- patient means an animal, preferably a mammal, and most preferably a human.
- compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
- the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
- Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- the oral compositions can also include adjuvants such as, for example, water or other solvents, solubil
- sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectables.
- the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- the rate of compound release can be controlled.
- biodegradable polymers include poly(orthoesters) and poly(anhydrides).
- Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
- compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and g
- Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
- the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
- the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
- Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
- the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
- buffering agents include polymeric substances and waxes.
- Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
- the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
- Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
- the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
- Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
- Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
- the compounds of the invention are useful as inhibitors of protein kinases, particularly for the JAK family kinases, ROCK and PKA.
- the compounds and compositions of the invention are inhibitors of JAK2 and JAK3.
- the compounds and compositions are useful for treating or lessening the severity of a disease, condition, or disorder where activation of a JAK family kinase, ROCK and/or PKA is implicated in the disease, condition, or disorder.
- the compounds and compositions are useful for treating or lessening the severity of a disease, condition, or disorder where activation of JAK2 or JAK3 is implicated in the disease, condition, or disorder.
- the disease, condition, or disorder may also be referred to as "JAK2-mediated disease", “JAK3-mediated disease”, “ROCK-mediated disease” or “PKA-mediated disease”, respectively.
- the present invention provides compounds or compositions comprising these compounds, for use in a method for treating or lessening the severity of a disease, condition, or disorder where activation of a JAK family kinase, ROCK or PKA, particularly JAK2 or JAK3, is implicated in the disease state.
- the activity of a compound utilized in this invention as an inhibitor of a JAK family kinase, ROCK or PKA, particularly JAK2 or JAK3, may be assayed in vitro, in vivo or in a cell line.
- In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of activated JAK2, JAK3, ROCK or PKA. Alternate in vitro assays quantitate the ability of the inhibitor to bind to JAK2, JAK3, ROCK or PKA.
- Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/kinase complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with the kinase of interest bound to known radioligands.
- detectably inhibit means a detectable change in JAK2, JAK3, ROCK or PKA activity between a sample comprising said composition and JAK2, JAK3, ROCK or PKA and an equivalent sample comprising JAK2, JAK3, ROCK or PKA, respectively, in the absence of said composition.
- JAK3-mediated disease or "JAK3-mediated condition”, as used herein means any disease or other deleterious condition in which JAK3 is known to play a role.
- a JAK3-mediated condition or disease also means those diseases or conditions that are alleviated by treatment with a JAK3 inhibitor.
- Such conditions include, without limitation, immune responses such as allergic or type I hypersensitivity reactions, asthma, autoimmune diseases such as transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis, neurodegenerative disorders such as Familial amyotrophic lateral sclerosis (FALS), as well as in solid and hematologic malignancies such as leukemias and lymphomas.
- FALS Familial amyotrophic lateral sclerosis
- JAK2-mediated disease or "JAK2-mediated condition”, as used herein means any disease or other deleterious condition in which JAK2 is known to play a role.
- a JAK2-mediated condition or disease also means those diseases or conditions that are alleviated by treatment with a JAK2 inhibitor.
- Such conditions include, without limitation, myeloproliferative disorders, including polycythemia vera, essential thrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome and systematic mast cell disease.
- ROCK-mediated disease or "ROCK-mediated condition”, as used herein, means any disease or other deleterious condition in which ROCK is known to play a role.
- a ROCK-mediated condition or disease also means those diseases or conditions that are alleviated by treatment with a ROCK inhibitor.
- Such conditions include, without limitation, hypertension, angina, angina pectoris, cerebrovascular contraction, asthma, peripheral circulation disorder, premature birth, cancer, erectile dysfunction, arteriosclerosis, spasm (cerebral vasospasm and coronary vasospasm), retinopathy (e.g., glaucoma), inflammatory disorders, autoimmune disorders, AIDS, osteoporosis, myocardial hypertrophy, ischemia/reperfusion-induced injury, endothelial dysfunction, Alzheimer's disease, or benign prostatic hyperplasia.
- hypertension angina, angina pectoris, cerebrovascular contraction, asthma, peripheral circulation disorder, premature birth, cancer, erectile dysfunction, arteriosclerosis, spasm (cerebral vasospasm and coronary vasospasm), retinopathy (e.g., glaucoma), inflammatory disorders, autoimmune disorders, AIDS, osteoporosis, myocardial hypertrophy, ischemia/reper
- such conditions in which ROCK is known to play a role include, without limitation, hypertension, cerebral vasospasm, coronary vasospasm, bronchial asthma, preterm labor, erectile dysfunction, glaucoma, vascular smooth muscle cell proliferation, myocardial hypertrophy, malignoma, ischemia/reperfusion-induced injury, endothelial dysfunction, Crohn's Disease and colitis, neurite outgrowth, Raynaud's Disease, angina, Alzheimer's disease, benign prostatic hyperplasia, or atherosclerosis.
- PKA-mediated disease or "PKA-mediated condition”, as used herein, means any disease or other deleterious condition in which PKA is known to play a role.
- PKA-mediated condition or disease also means those diseases or conditions that are alleviated by treatment with a PKA inhibitor.
- PKA-mediated diseases or conditions include, but are not limited to, proliferative disorders and cancer.
- the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
- the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
- the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects).
- additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition are known as "appropriate for the disease, or condition, being treated".
- the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
- the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
- the present invention in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
- the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
- Vascular stents for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury).
- patients using stents or other implantable devices risk clot formation or platelet activation.
- a pharmaceutically acceptable composition comprising a kinase inhibitor.
- Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562 ; 5,886,026 ; and 5,304,121 .
- the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
- the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
- Another aspect of the invention relates to inhibiting JAK2, JAK3, ROCK or PKA activity in a biological sample, which method comprises contacting said biological sample with a compound of formula I or a composition comprising said compound.
- biological sample is an ex vivo or in vitro sample, and includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
- Inhibition of JAK2, JAK3, ROCK or PKA kinase activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organtransplantation, biological specimen storage, and biological assays.
- Step 1 Compound A (1-(tert Butoxycarbonyl)-3-piperidine carboxylic acid) (4.60g, 20.0 mMol) was suspended in 40 ml of CH 2 Cl 2 . Added was EDCI (4.60 g, 24.0 mMol), followed by N,O-Dimethylamine (HCl) (2.34 g (24.0 mMol) and catalytic DMAP. The resulting mixture was allowed to stir at room temperature overnight. All volatiles were removed at reduced pressure. The residue was dissolved in saturated aqueous NaHCO 3 solution and EtOAc. The layers were separated and the organic was washed with brine, dried over MgSO 4 , filtered and evaporated to dryness.
- Step 2 To a solution of compound B (4.7 g, 17.2 mMol) in 70 ml of THF at 0°C (under N 2 ) was added a 3.0 M (11.5 ml, 34.5 mMol) solution of Methyl Magnesium Bromide in THF. After the addition was complete, the cooling bath was removed and the resulting mixture was allowed to rise to room temperature where it was allowed to stir overnight. The resulting mixture was quenched with a saturated aqueous KHSO 4 solution and diluted with EtOAc. The organic phase was washed with brine, dried over MgSO 4 , filtered and evaporated to dryness.
- Step 3 Compound C (2.37 g, 10.4 mMol) was dissolved in 5.0 ml of THF and added (under N 2 ) to a solution of LiHMDS (13.0 ml, 13.0 mMol) at -78°C (IPA-dry ice bath). After 30 min., added was 2-[N,N-bis(trifluoromethylsulfonyl) amino]pyridine (4.11g, 11.5mMol) and after 10 min. the cooling bath was removed. The resulting mixture gradually rose to room temperature where it was allowed to stir overnight. The resulting mixture was quenched with saturated aqueous KHSO 4 solution and diluted with EtOAc.
- Step 4 Compound D (2.93 g, 8.2 mMol) was dissolved in 30 ml of toluene. Added was Bis(Pinacoloto)diboron (2.07 g, 8.2 mMol) followed by Triphenyl phosphine (117.3 mg, 0.44mMol) and Potassium phenoxide (1.48 g, 11.2 mMol). The RM was degassed with Ar for 5 min. Added was trans-Dichlorobis (triphenylphosphine)palladium (II) (157.0 mg, 0.22 mMol) and the resulting mixture was allowed stir at 55°C for 3 hours.
- Step 5 Compound E (45.7 mg, 0.14 mMol) was dissolved in 1.0 ml of DME. Added was 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (20.8 mg, 0.14 mMol) followed by a 2.0 M solution of Na 2 CO 3 (200uL, 0.4 mMol). The resulting mixture was degassed with Ar for 5 minutes and added was catalytic tetrakis triphenylphosphine palladium (0). The resulting mixture was warmed to 160°C via microwave irradiation. After 10 minutes, the resulting mixture was cooled to room temperature. The resulting mixture was diluted with H 2 O and EtOAc.
- Step a 4-(1-Ethoxy-vinyl)-7-(toluene-4-sulfonyl)-7 H -pyrrolo[2,3-d]pyrimidine: [10g, 25mmol] of 4-Iodo-7-(toluene-4-sulfonyl)-7 H -pyrrolo[2,3- d ]pyrimidine (as described above) was dissolved/suspended in 200mL of dry toluene along with [2.0g, 2.85mmol] of palladium (II) bis-triphenylphosphine dichloride. The mixture was purged with nitrogen gas for -5 minutes before mixture was heated to 90°C in an oil bath under an atmosphere of nitrogen gas.
- Step b 1-[7-(Toluene-4-sulfonyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl]-ethanone: [7.25g, 21.12mmol] of 4-(1-Ethoxy-vinyl)-7-(toluene-4-sulfonyl)-7 H- pyrrolo[2,3- d ]pyrimidine was dissolved in 50mL each of methanol and THF and stirred with 10mL of 6N HCL for 4.0 hours at ambient temperature. The solvents were removed under reduced pressure and the residue was partitioned between dichloromethane and saturated sodium hydrogen carbonate solution.
- Step c 2-Bromo-1-[7-(toluene-4-sulfonyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl]-ethanone: [5.95g, 18.88mmol] of 1-[7-(Toluene-4-sulfonyl)-7 H- pyrrolo[2,3- d ]pyrimidin-4-yl]-ethanone was dissolved/suspended in 90mL of glacial acetic acid and [7.53mL, 10.197g, 37.76mmol] of 30% hydrogen bromide in acetic acid.
- Steps d, e Conversion of the bromide may be accomplished upon nucleophilic displacement with primary or secondary amines (i.e., step d ) or upon treatment with an alcohol (i.e., step e ) under basic conditions.
- Step f The compound is deprotected as described for Compound 1.
- Steps a,b 4-Bicyclo[2.2.1]hept-2-yl-7 H -pyrrolo[2,3- d ]pyrimidine: To a solution of N-tosyl-4-chlorodeazapurine (40 mg, 0.13 mmol) in anhydrous THF (0.5 mL) was added an appropriate alkylzinc halide (e.g., exo-2-norbornylzinc bromide [0.40 mL, 0.5 M]) and the mixture is stirred overnight at room temperature. Then the mixture is heated to 80°C for an additional 1.5h and cooled to room temperature.
- an appropriate alkylzinc halide e.g., exo-2-norbornylzinc bromide [0.40 mL, 0.5 M]
- the reaction mixture is treated with NaOMe (200 uL, 0.5 M) in MeOH at 50°C for 1.5 h before work up.
- Rochelle's salt is added and the mixture is extracted repeatedly with EtOAc. The organic layer is filtered and concentrated. The crude residue is purified by HPLC to provide the Compound 26.
- Table 4 depicts exemplary 1 H-NMR data (NMR) and liquid chromatographic mass spectral data, reported as mass plus proton (M+H), as determined by electrospray, and retention time (RT) for certain compounds of the present invention, wherein compound numbers in Table 4 correspond to the compounds depicted in Table 3 (empty cells indicate that the test was not performed): Table 4 Cmpd # M+H + LC-MS R t 1 H NMR 2 Lot 1: 200.00 Lot1: 1.93 Lot 1: (500 MHz, CDCl3) 8.92 (br s, 1H), 8.81 (s, 1H), 7.26 (burried dd, 1H), 6.86 (m, 1H), 6.72 (dd, 1H), 2.70 (m, 2H), 2.34 (m, 2H), 1.84 (m, 2H), 1.76 (m, 2H) 9 301.00 2.05 (CDCl3) 10.07 (br s, 1H), 8.86 (s, 1H), 7.35 (d, 1H), 6.
- Substrate concentrations in the assay were 5 ⁇ M ATP (200 uCi/ ⁇ mole ATP) and 1 ⁇ M poly(Glu) 4 Tyr. Reactions were carried out at 25 °C and 1 nM JAK3.
- the final poly(Glu) 4 Tyr concentration is 15 ⁇ M, and final ATP concentration is 12 ⁇ M.
- Final concentrations of the components of the coupled enzyme system are 2.5 mM phosphoenolpyruvate, 350 ⁇ M NADH, 30 ⁇ g/ml pyruvate kinase and 10 ⁇ g/ml lactate dehydrogenase.
- Compounds are screened for their ability to inhibit ROCK using a standard radioactive enzyme assay. Assays are carried out in a solution containing 100 mM HEPES (pH 7.5), 10 mM MgCl 2 , 25 mM NaCl, 2 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay are 13 ⁇ M [ ⁇ - 33 P] ATP (25mCi 33 P ATP/mmol ATP, Perkin Elmer, Cambridge, MA /Sigma Chemicals, St Louis, MO) and 27 ⁇ M Myelin Basic Protein (MBP). Final enzyme concentration in the assay is 5 nM ROCK. Assays are carried out at room temperature.
- 1.5 ⁇ l of DMSO stock containing serial dilutions of the compound of the present invention (concentrations ranging from 10 ⁇ M to 2.6nM) is placed in a 96 well plate.
- 50 ⁇ l of Solution 1 (100 mM HEPES (pH 7.5), 10 mM MgCl 2 , 26 mM [ ⁇ - 33 P] ATP) is added to the plate.
- the reaction is initiated by addition of 50 ⁇ l of Solution 2 (100 mM HEPES (pH 7.5), 10 mM MgCl 2 , 4 mM DTT, 54 mM MBP and 10 nM ROCK).
- the reaction is quenched with 50 ⁇ L of 30% trichloroacetic acid (TCA, Fisher) containing 9mM ATP. Transfer of 140 ⁇ L of the quenched reaction to a glass fiber filter plate (Coming, Cat. No.3511) is followed by washing 3 times with 5 % TCA. 50 ⁇ L of Optima Gold scintillation fluid (Perkin Elmer) is added and the plates are counted on a Top Count (Perkin Elmer). After removing mean background values for all of the data points the data is fit using Prism software to obtain a K i (app).
- TCA trichloroacetic acid
- An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ATP, and the test compound of the present invention. 55 ⁇ l of the stock solution was placed in a 96 well plate followed by addition of 2 ⁇ l of DMSO stock containing serial dilutions of the test compound of the present invention (typically starting from a final concentration of 5 ⁇ M). The plate was preincubated for 10 minutes at 30°C and the reaction initiated by addition of 5 ⁇ l of ATP (final concentration 50 ⁇ M). Initial reaction rates were determined with a Molecular Devices SpectraMax Plus plate reader over a 15 minute time course. IC 50 and K i data were calculated from non-linear regression analysis using the Prism software package (GraphPad Prism version 3.0a for Macintosh, GraphPad Software, San Diego California, USA).
- Table 5 depicts enzyme inhibition data (K i ) for certain exemplary compounds.
- Compound numbers in Table 5 correspond to those compounds depicted in Table 3.
- “A” represents a K i of less than 0.5 ⁇ M
- “B” represents a K i of between 0.5 and 5.0 ⁇ M
- “C” represents a K i of greater than 5.0 ⁇ M.
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GB9604361D0 (en) * | 1996-02-29 | 1996-05-01 | Pharmacia Spa | 4-Substituted pyrrolopyrimidine compounds as tyrosine kinase inhibitors |
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ATE399766T1 (de) * | 2000-10-20 | 2008-07-15 | Eisai R&D Man Co Ltd | Stickstoff enthaltende aromatische heterozyklen |
US7407962B2 (en) * | 2003-02-07 | 2008-08-05 | Vertex Pharmaceuticals Incorporated | Heteroaryl compounds useful as inhibitors or protein kinases |
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DE602006004844D1 (de) | 2009-03-05 |
JP5227032B2 (ja) | 2013-07-03 |
RU2007132908A (ru) | 2009-03-10 |
JP2009102361A (ja) | 2009-05-14 |
ATE420883T1 (de) | 2009-01-15 |
JP2008528705A (ja) | 2008-07-31 |
KR20070104641A (ko) | 2007-10-26 |
ZA200707342B (en) | 2009-03-25 |
MX2007009429A (es) | 2008-03-18 |
RU2434871C2 (ru) | 2011-11-27 |
EP1844050A1 (en) | 2007-10-17 |
IL184898A0 (en) | 2007-12-03 |
CA2596830A1 (en) | 2006-09-14 |
US20140171454A1 (en) | 2014-06-19 |
US20070004762A9 (en) | 2007-01-04 |
US20060183761A1 (en) | 2006-08-17 |
US8633205B2 (en) | 2014-01-21 |
HK1116349A1 (en) | 2008-12-19 |
NO20074431L (no) | 2007-08-31 |
WO2006096270A1 (en) | 2006-09-14 |
AU2006221065A1 (en) | 2006-09-14 |
CN101142218B (zh) | 2013-02-06 |
ES2320487T3 (es) | 2009-05-22 |
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